Every year breast cancer causes the death of around 40,000 women in the United States, highlighting the need to develop new therapies to fight this disease. A limiting aspect of cancer research is the high rate of failure to translate exciting preclinical laboratory data into improved patient survival in the clinic. A number of factors contribute to this, including differences between tumors in patients and the tumor models used in a laboratory setting. Furthermore, new drugs are usually evaluated in the clinic in combination with established chemotherapy regimens, yet how these new agents interact with the established treatments remains poorly understood. Thus, some new drugs may antagonize the efficacy of chemotherapy, leading to disappointing anti- tumor responses. We propose to use this challenge as a rationale for a novel approach to drug screening. The approach evaluates drug libraries on breast cancer cells that have been exposed to clinically used chemotherapy (specifically the chemotherapeutic drug paclitaxel). In Specific Aim 1, LM2-4 human breast cancer cells will be used to screen for drugs that impair the recovery of cells pre-exposed to paclitaxel. In Specific Aim 2, we will use xenograft models to test the ability of different candidate drugs to inhibit the growth of breast tumors treated with paclitaxel. Our hypothesis is that drugs that inhibit the recovery of breast cancer cells exposed to paclitaxel are ideally suite for maximizing the anti-cancer benefit of this chemotherapy. Overall this project will identify compounds that can improve the efficacy of clinically used chemotherapy, which should ultimately lead to an increase in the overall survival for those breast cancer patients receiving paclitaxel based therapies.